# Role of MST/Hippo kinase inactivation in driving fusion-positive rhabdomyosarcoma

> **NIH NIH F31** · DUKE UNIVERSITY · 2020 · $34,340

## Abstract

Abstract
Rhabdomyosarcoma (RMS), a cancer related to the skeletal muscle lineage, is the most common soft-tissue
sarcoma of childhood and adolescence. Despite intergroup clinical trials, survival for high-risk groups has not
improved in over four decades. Children with the alveolar variant of RMS, and accompanied by the fusion
protein PAX3-FOXO1 (PF), have a particularly dismal outcome of <10% survival when metastatic. An
improved understanding of the aberrant signaling underlying PF-RMS is vital for the development of new
therapies. This work seeks to exploit a novel genetically engineered mouse model (GEMM) of PF-RMS that
was recently developed in our laboratory. This new 9-allele GEMM, in which both isoforms of the Hippo kinase
(also known as MST tumor suppressor) are deleted, generates PF-RMS tumors with a shorter latency and
increased aggressiveness compared to earlier GEMMs. This project evolved from our prior investigations
showing that PF contributes to RMS in part by disabling the Hippo tumor suppressor pathway. In summary, we
defined a PF→RASSF4 ⊣MST axis, in which PF transcriptionally upregulates expression of a scaffold protein
known as RASSF4, which in turn binds to and inhibits the Hippo tumor suppressor kinase MST1. To build upon
these findings, we sought to evaluate the consequences of conditional loss of both MST1 and MST2 alleles in
a GEMM of PF-RMS. The resulting GEMM (which we term MSTNull) is the product of this effort. Important
observations from this new GEMM include that loss of MST accelerates PF-RMS tumorigenesis and increases
penetrance, and signals not to the canonical Hippo protein YAP1, but to the little-studied protein MOB1. We do
not know how MST loss contributes to PF-RMS tumorigenesis. Nor do we know whether silencing of MST1 or
MST2 is more critical. Finally, although we have zeroed in on non-canonical signaling, we do not know which
genes/proteins are downstream from this PF→RASSF4 ⊣MST axis. We therefore propose the following
Specific Aims: (1) determine the cellular phenotypic consequences of MST loss in PF-RMS, (2) investigate the
unique contributions of MST1 and MST2 loss to PF-RMS, and (3) identify the downstream genes/proteins that
mediate the increased tumorigenesis of the PF→RASSF4 ⊣MST axis. Completion of these aims will provide
critical foundational information on the mechanisms through which the PF→RASSF4 ⊣MSTaxis supports PF-
RMS tumorigenesis. The fundamental goal is to identify novel therapeutic targets for this difficult-to-cure
sarcoma.

## Key facts

- **NIH application ID:** 10068928
- **Project number:** 1F31CA254301-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kristianne Oristian
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,340
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068928

## Citation

> US National Institutes of Health, RePORTER application 10068928, Role of MST/Hippo kinase inactivation in driving fusion-positive rhabdomyosarcoma (1F31CA254301-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068928. Licensed CC0.

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